The invention relates generally to medical manipulation of the human immune response to ameliorate or alter signs or symptoms of inflammatory conditions or diseases relating to inflammation, immunity or autoimmunity. More specifically, the invention relates to a method of potentiating interleukin-10 (IL-10) mediated inhibition of cytokine production by mammalian T-cells. The method includes the coadministration to the mammal of effective amounts of interleukin-4 (IL-4) and IL-10.
The immune system is diverse and complex. It includes a multitude of natural and adaptive immune mechanisms and reactions. For practical purposes, the immune system is often thought of in terms of humoral and cellular immunity. Humoral immunity refers broadly to antibody production and actions by B-cells including plasma cells. Cellular immunity is mediated by cells including T-cells, monocytes, macrophages and histiocytes. T-cells and B-cells are two broad categories of lymphocytes. T-cells may be further categorized according to their various functions or markers. For instance, T-cells can be classified as T helper cells or T suppressor cells. Additionally, T-cells can be activated to become cytotoxic or to perform other more specialized functions. Normally, T-cells and B-cells have interactions that may regulate each other's activity to some extent.
For instance, for different antigens either cellular or humoral responses may predominate in a mutually exclusive fashion. The severity of some diseases, e.g., leprosy, leishmaniasis, and some types of autoimmunity, may be due the inappropriate dominance of one class of response over the other. Mosmann and Coffman, Immunol. Today, 8:223-227 (1987); Mosmann and Coffman, Ann. Rev. Immunol., 7:145-173 (1989); Parish, Transplant. Rev, 13:35-66 (1972); and Liew, Immunol. Today, 10:40-45 (1989).
Among cell mediated immune mechanisms, the phenomena of delayed type hypersensitivity (DTH) is an example. Many diseases are associated with inappropriate immune responses. Examples include tissue rejection such as kidney transplant rejection and graft versus host disease (GVHD), parasitic diseases such as leishmaniasis and immune disorders associated with the Major Histocompatibility Complex (MHC) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myesthesia gravis, insulin dependent diabetes melitis or Type I diabetes, thyroiditis and other diseases including autoimmune diseases and diseases of abnormal or inappropriate immune response or immune regulation.
One of the mechanisms by which the immune system normally regulates itself includes the production of proteins called cytokines. For example, lymphokines are cytokines produced by T-cells and some B-cells, and monokines are cytokines produced by monocytes. Cytokines, which may be glycosylated, mediate numerous immune responses.
IL-4 is a cytokine capable of stimulating production of antibody producing B-cells and which also promotes growth of killer T-cells or cytotoxic T-cells. Additionally, it can inhibit the activity of T-helper cells type 1 (Th1). This in turn may inhibit production of more B-cells or antibody production by more B-cells. Thus, IL-4 is part of an internal regulatory mechanism.
IL-10 is a cytokine capable of a number of actions or effects. IL-10 has been isolated from both mouse and human cells and is thought to be involved in controlling the immune responses of different classes or subsets of T helper (Th) cells. Th cells can be divided into different subsets that are distinguished by their cytokine production profiles. Th1 T cell clones produce interleukin (IL)-2 and interferons such as (IFN)-.gamma., whereas Th2 cell clones secrete IL-10, IL-4 and IL-5, generally following activation by antigens or mitogenic lectins. Both classes of Th cell clones produce cytokines such as tumor necrosis factor (TNF)-.alpha., IL-3 and granulocytemacrophage colony stimulating factor (GM-CSF). A third category of Th cells (Th0) produces IL-2, IFN-.gamma., IL-4, IL-5, TNF-.alpha., IL-3 and GM-CSF simultaneously.
The different cytokine production patterns of Th1 and Th2 cells reflect their helper functions. Th1 cells are predominantly involved in delayed-type hypersensitivity responses, whereas Th2 cells are associated with antibody production. Since antibody (Th2 pathways) and delayed-type hypersensitivity (Th1 pathways) responses are often mutually exclusive, Th1 and Th2 cells are thought to have cross-regulatory effects. IFN-.gamma. produced by Th1 cells inhibits proliferation of Th2 cells, and IL-10 produced by Th2 cells inhibits cytokine synthesis, especially IFN-.gamma. and IL-2 production, by Th1 cell clones.
Some sets of cytokines are separately associated with DTH reactions and humoral immune responses. Cher et al., J. Immunol. 138:3688-3694 (1987); and Mosmann et al. (1987 and 1989, cited above). Diseases associated with these classes of response may be caused by inappropriate production of associated sets of cytokines.
In an example of inappropriate cytokine production, evidence suggests that excessive production of gamma interferon (IFN-.gamma.) is responsible for major histocompatibility complex (MHC) associated autoimmune diseases: Hooks et al., New England J. Med., 301:5-8 (1979) (elevated serum levels of IFN-.gamma. correlated with autoimmunity); Basham et al. J. Immunol. 130:1492-1494 (1983) (IFN-.gamma. can increase MHC gene product expression); Battazzo et al., Lancet, 1115-1119 (Nov. 12, 1983) (aberrant MHC gene product expression correlated with some forms of autoimmunity); Hooks et al., Ann. N.Y. Acad. Sci. 350:21-32 (1980) (higher IFN-.gamma. levels correlated to greater severity of disease in SLE patients, and histamine-release enhancing activity of interferon can be inhibited by anti-interferon sera); and Iwatani et al., J. Clin. Endocrin. and Metabol. 63:695-708 (1986) (anti-IFN-.gamma. monoclonal antibody eliminated the ability of leucoagglutinin-stimulated T cells to induce HLA-DR expression). Possibly, excess IFN-.gamma. causes inappropriate expression of MHC gene products which, in turn, causes autoimmune reactions against the tissues inappropriately expressing the MHC products and displaying autoantigens in the context of the products.
In view of the above, agents that could shift the dominance of one class of immune response to the other are desirable. Particularly, manipulation of the synthesis of cytokines, such as IFN-.gamma., would be advantageous for therapy. Such agents would be applicable to treatment of diseases associated with inappropriate or inadequate immune responses, such as tissue rejection, leishmaniasis and other parasitic diseases, and MHC associated immune disorders including rheumatoid arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, insulin-dependent diabetes mellitus, thyroiditis, and the like.